The roles of circulating immunoreactive parathyroid hormone (iPTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] in the synthesis of the uremic skelton were studied in a variety of patients with end-stage renal disease. The first group consisted of 14 patients who had received time-spaced tetracycline skeltal markers and whose bone biopsies exhibited the features of severe osteitis fibrosa. These patients had elevated circulating inorganic phosphorus levels and markedly increased iPTH. The second group was comprised of 11 patients in whose bone biopsies osteomalacia predominated. These patients were generally normophosphatemic and had relatively low levels of iPTH. The rate of synthesis per U bone-forming surface, as determined by morphometric techniques, was approximately 3 times normal (P < 0.001) in the severely hyperparathyroid patients, two of whom were anephric. This parameter of bone formation was no greater than normal in the group of osteomalacic patients. Another group of 39 randomly selected patients with endstage renal disease underwent bone biopsy after a single course of tetracycline. Calcification front formation, which was normal in 19 of these patients, was directly (P < 0.005) related to the log iPTH. Finally, 2 totally parathyroidectomized, chronically uremic patients were treated with 50-100 μg 25-hydroxy vitamin D3/day. Sequential bone biopsies taken during prolonged therapy failed to demonstrate a skeletal response to this metabolite. These data indicate that: 1) the rate of bone formation is increased in chronically uremic patients with severe hyperparathyroidism despite the absence of 1,25(OH)2D; 2) calcification front formation is directly proportional to log iPTH in chronic uremia; 3) many uremic patients have normal calcification front formation, calling into question the assumption that end-stage renal disease is almost universally accompanied by osteomalacia; and 4) the total absence of PTH may preclude the therapeutic response of the uremic skeleton to a generally beneficial metabolite of vitamin D.